Alzheimer disease and amyotrophic lateral sclerosis: An etiopathogenic connection

Xiaochuan Wang, Julie Blanchard, Inge Grundke-Iqbal, Jerzy Wegiel, Han Xiang Deng, Teepu Siddique, Khalid Iqbal*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

21 Scopus citations

Abstract

The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) is well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I 2 PP2A. In AD brain, PP2A activity is compromised, probably because I 2 PP2A is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I 2CTF, and both fragments inhibit PP2A. Here, we analyzed the spinal cords from ALS and control cases for I 2 PP2A cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I 2 PP2A into I2NTF and I 2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I 2 PP2A, we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I 2CTF. AAV1-I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5-8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10-14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I 2 PP2A and the potential of I 2 PP2A -based therapeutics for these diseases.

Original languageEnglish (US)
Pages (from-to)243-256
Number of pages14
JournalActa Neuropathologica
Volume127
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Abnormal hyperphosphorylation of tau
  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • Guam Parkinsonism dementia complex
  • Inhibitor-2 of protein phosphatase-2A, I /SET
  • Protein phosphatase-2A

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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